CS212252B2 - Method of making the new derivatives of the phenoxyalkylcarboxyl acids - Google Patents

Description

In particular, the invention relates to a process for the preparation of compounds of the formula II which are novel industrial products useful in medicine.

According to the process of the present invention, it is possible to obtain p - [(α-alkyl-α-hydroxy) methyl] -, p - [(α-cycloalkyl-α-hydroxy) methyl] -, β - [(α-aryl-α-hydroxy) methyl] -, p - [(α-heteroaryl-α-hydroxy) methyl] phenoxyalkylcarboxylic acid, and derivatives thereof.

The acids and their derivatives obtainable by the process according to the invention can be represented by the general formula II,

where

A represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or cyclohexyl group or one of the groups of the general formulas

c ₂ h ₅ wherein each of the substituents X 1, X ₂ and X ₁ , which are the same or different, represents hydrogen, chloro, bromo, fluoro, trifluoromethyl, amino, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of st up to 4 carbon atoms, benzyloxy, acetylamino, acetoxy, CHO, COOH, -OC (CH3) -COM, where M is hydroxyl or alkoxy of up to 4 carbon atoms,

Xg is oxygen or sulfur and Χγ is hydrogen, chlorine or bromine, each of R, X ^ and Xg, which may be identical or different, represents a hydrogen atom or a C1-C4 alkyl group,

Y represents hydrogen, hydroxyl, straight-chain or branched alkoxy of 1 to 12 carbon atoms, cycloalkyloxy of 3 to 8 carbon atoms, alkylthio of 1 to 4 carbon atoms, 2,3-dihydroxypropyloxy, 4- (2,2-dimethyl) -1,3-dioxolanyl) methyleneoxy of formula

O-CH _2q - ₍ ° x °

HgC CHg phenoxy optionally substituted with chlorine at the 4-position, further 3-pyridylmethyleneoxy, 5- (2-methyl-3-hydroxy-4-hydroxymethyl) pyrimidylmethyleneoxy of formula

group NZjZg, ΝΗ0Η ₂ 0Η ₂ ΝΖ, Ζ ₂ OCHgCHgNZjZg, ° ^(CH2 ^ m ^C0NZ 1 ^Z 2 'wherein a is from 1 to 4 carbon atoms and each R Zi and Z ₂ represents an alkyl group having 1 to 4 carbon atoms or Z ₁ and Z ₂ together with the nitrogen atom to which they are attached form an N-heterocyclic group of 5 to 7 members, which optionally contains, as further heteroatom, oxygen or nitrogen and which is optionally substituted by a C1-C4 alkyl radical or a phenyl radical, optionally substituted with halogen, or a group of the formula

CH ₃

-O- (CH ₂ ) ₃ -O ₂ CC -Ο-θ-C 1 CH ₃ o and R ^z represents a hydrogen atom, a C 1 -C 4 alkyl group or an acetyl group.

It is also within the scope of the invention to prepare the acid addition salts of said acids.

Alkyl, alkoxy and alkylthio groups are straight or branched chain hydrocarbon radicals. Of the lower C 1 -C 4 alkyl groups, the preferred group for X 1, X ₂ , X ₁ , X ₁ , X ₁ , X 1, R 2 and R 1 is methyl, the preferred groups for Z 1 and Z ₂ are methyl, ethyl, isopropyl and n-butyl, and preferred atoms for Xg are oxygen and sulfur.

Of the C 1 -C 12 alkoxy groups, methoxy-, ethoxy-, isopropoxy-, isobutyloxy-, tert-butyloxy-, 2-pentyloxy-, 3-pentyloxy-, 1-octyloxy- with 1-dodeoyloxy are preferred.

Preferred C 3 -C 8 cycloalkyloxy groups are, in particular, cyclopentyloxy, cyclohexyloxy and cyclooctyloxy.

N-heterocyclic, optionally substituted NZ ₁ groups of 5 to 7 members are especially pyrrolidine, morpholine, piperidine, 4-methylpiperidine, 4-methylpiperazine, 4-phenylpiperazine, 4-p-chlorophenylpiperazine and hexamethylenimine groups.

Of the Y groups containing at least one nitrogen atom, the preferred groups for Y = K ₂ , Z ₂ are NiCH 3, N (C ₂ H 8) ₂ , N (n C ₄ H 8) ₂ , piperidine and morpholine; preferred groups for Y = NHCHgCHgNZjZg are 2-dimethylaminoethylamino and 2-dimethylaminoethylamino groups; Preferred groups for Y = ^ OCI compounding NZjZg 3 ^SOU hexamethyleniminoethoxyskupina, morpholinoethoxy, piperidinoethoxy and 2-diethylaminoethoxy.

Addition salts are ammonium salts and acid addition salts formed with the compounds of formula (II) which contain at least one amino group. Acid addition salts may be prepared by reaction of a base with a mineral or organic acid, in particular hydrochloric, fumaric, maleic and oxalic acid.

The process using a compound in which A is a substituted substituted phenyl is, of course, directly applicable to compounds in which A is heteroaryl.

The compounds of the formula II prepared by the process of the invention are listed in Table II, the starting compounds of the formula I in Table I and the starting ketones which are common starting materials for all products prepared by the process of the invention are shown in Tables III and IV.

The compounds produced by the method of the invention are particularly useful for the treatment of hyperlipaemia; is an active ingredient of compositions comprising, together with a physiologically acceptable carrier, a pharmaceutically effective amount of at least one compound of Formula I or II or a nontoxic addition salt thereof.

The present invention provides a process for the preparation of novel phenoxyalkylcarboxylic acid derivatives of formula (II) wherein A, X X, Xg, R, R * and Y are as defined above, as well as their editorial salts, characterized in that the compound of formula (I)

where

A, X ^, Xg, R a and Y are as defined above, reduced by treatment with a reducing agent, and the resulting product of formula (II) wherein R vod is hydrogen and A, X ^, X R, R Y and Y are as defined above, optionally undergoing an etherification or acetylation reaction, whereupon the product obtained is optionally converted into an addition salt.

The method of the invention is illustrated in a broader context below.

'1

The process according to the invention for the preparation of the compounds of the formula II can be illustrated by the following reaction scheme:

In this process, the reduction of a compound of formula I to a compound of formula II is preferably carried out using potassium borohydride, but it is also possible to use a metal isopropylate.

The starting compounds of the formula I can be obtained by the following processes:

A - Direct recovery of compounds of formula I

a) Methods using Friedel-Crafts reactions

Method Aal:

ACOCI +

CH,

AND

O - C - COY Lewis _; I acid (III) (IV) (I)

The reactants III and IV, which are known and commercially available, are reacted in a solvent environment particularly suitable for carrying out the Friedel-Crafts reaction (carbon disulfide, dichloroethane, benzene, methylene chloride, nitrobenzene, nitromethane, optionally compound IV itself). The catalyst is a Lewis acid selected from the group consisting of aluminum chloride, tin tetrachloride, titanium tetrachloride, boron trifluoride and antimony fluoride. Antimony trifluoride must be used when one of the substituents of group A, namely X1, X8 or X4, is a trifluoromethyl radical.

If one of the substituents X1, X8 or X4 is NH8 or OH, this method cannot be used directly;

it is necessary to either protect these groups with acetyl as NH 4 -CH 2 and OC-CH 3 or to carry out a Friedel-Crafts reaction with a compound III containing a group from which an NH 8 or OH group is readily obtained: e.g. NOg to NHg is a classical reduction, conversion of NOg to OH can be achieved by a method known per se). Regarding the Y substituents of compound IV which allow this type of reaction, the preferred substituents are OCH3, OC8H3, with the exclusion of OH.

Method Aa2:

* 5

-COY

CH,

Lewis acid

All remarks made in the previous method are valid here as well, and should be followed accordingly as described in this reaction scheme. This scheme applies only where A is aryl and heteroaryl. Regarding compounds for the compounds of formula ^C-II-Q '

CH,

AND

-cCOY is obtained in a known manner by one of the following reaction procedures:

and

212252 6

(b) Procedures using an organomagnesium compound

These processes utilize the property of organomagnesium compounds to provide ketones when reacted with nitriles or acid chlorides: to give ketones I; If an aldehyde is reacted with the same organomagnesium compound in place of the nitrile or the acid chloride, the alcohol of formula II is obtained directly.

Abl Method:

The condensation is carried out at a temperature in the range of -10 to +30 ° C in a solvent medium in which an organomagnesium compound of formula VI (ether or tetrahydrofuran) has been prepared. The organomagnesium compound of formula VI can in all cases be prepared from a compound of formula

after conversion to the salt by treatment with sodium hydroxide NaOH (Y = ONa) or, more preferably, with a compound of the formula CH 2 MgJ or C 8 H 9 MgBr (Y = OMgJ or OMgBr).

The preparation of the organomagnesium compound, in fact the conversion of Br to MgBr, is achieved by reacting the thus protected bromo derivative with magnesium in an ether or anhydrous tetrahydrofuran environment. However, it is preferred to carry out both of these steps simultaneously by exchange with CH 2 MgJ to obtain a derivative according to the equation β, -Λ

CHo

AND

OC-CO ₂ H + 2 CH ₃ MgJ R

JMg—

CH ³ I (VI)

Example illustrating this method:

Preparation of 2 - [(p-benzoyl) phenoxy] -2-methylpropionic acid

A 500 ml flask was charged with 26 g (0.1 mol) of 2 - [(p-bromo) phenoxy] -2-methylpropionic acid, which was dissolved in 200 ml of anhydrous tetrahydrofuran. The solution was cooled in an ice bath and 0.2 mole of methylmagnesium iodide prepared in anhydrous tetrahydrofuran was slowly added. After the addition was complete, the temperature was allowed to rise to room temperature and the solution was stirred at this temperature for 1.5 hours. A solution of 4.1 g (0.1 mol of benzonitrile in 20 ml of tetrahydrofuran) was slowly added dropwise, and the resulting mixture was stirred at room temperature for 2.5 hours, then poured into 500 ml of 10% hydrochloric acid, cooled with 500 g of ice. After washing, drying and decolorizing the ether phase, the solvent is evaporated off under reduced pressure and the oily residue is placed in a vacuum desiccator. in an amount of 22 g, i.e. 77% of theory, melting point 130 ° C.

Ab2 Method:

Use of acid chloride

ACOCI + BrMg

(AND)

This time, the condensation is carried out at a lower temperature, in the range of -30 to +10 ° C, taking care that the acid chloride is never in excess in the reaction mixture; it is therefore necessary to add the acid chloride to the organomagnesium compound.

On the other hand, the use of a cuprous halide (cuprous bromide, cuprous chloride, cuprous iodide), which is reacted in a molar ratio with the compound of formula VI, very often yields very good yields before the acid chloride is added. The preparation of the compound of formula (VI) is carried out as described above.

Example

Preparation of 2-f (p-4'-fluorobenzoyl) phenoxy] -2-methylpropionic acid

In a 500 ml flask, 0.1 mole of the compound of the formula is prepared as described above

CH,

I ^J

OC-CO ₂ M _g J

The contents of the flask were then cooled to -25 ° C and copper (I) iodide (9 g, 0.1 mol) was added. A solution of 10.7 g (0.1 mol) of p-fluorobenzoyl chloride in 50 ml of tetrahydrofuran is then added dropwise via bromination funnel over 30 minutes. The reaction medium is then allowed to rise to 15-20 ° C and the reaction mixture is poured into 500 ml. of a mixture of 10% hydrochloric acid with 500 g of ice. After extraction with ether, washing, drying and decolorization of the combined ether phases, the solvent is evaporated under reduced pressure. 20 g of the acid produced are obtained in the form of a solid residue, m.p. 160 DEG. Yield 68%.

Ab3 Method:

Use of aldehyde

The condensation is carried out at a temperature in the range of -10 to +30 ° C in the solvent medium used to prepare the organomagnesium compound of formula VI (ether or tetrahydrofuran). The compound of formula (VI) is prepared as described above.

Example

Preparation of 2- [p- (ap-nitrobenzyl-α-hydroxy) methyl] phenoxy-2-methylpropionic acid of formula ₂ n

OH

AND

CH

CH

I-cI

- after ₂ h

CH

In a 500 ml flask, 0.1 mol of the above compound was prepared as described above. The reaction medium is then cooled with an ice lesion and a solution of 15 g (0.1 mol) of p-nitrobenzaldehyde in 30 ml of tetrahydrofuran is slowly added at this temperature. The reaction mixture was then stirred at room temperature for 2 hours, then hydrolyzed and worked up as above. 21 g of the acid produced are obtained in the form of a solid, m.p. 148 DEG. Yield: 64%.

It is not possible to obtain directly compounds of formula I or II in which Ab represents a group by methods Ab1, Ab2 or Ab3.

wherein X 1, X ₂ or X ₁ would not be compatible with the organomagnesium reaction. This is the case where Xi, X ₂ or X @ ₂ represent NH and OH. In this case, the compounds of formula (I) and (II) are prepared via an intermediate compound wherein X 1, X ₂ or X ₁ are nitro, as described for method Aa1.

(c) Procedures using phenol

Direct access to isobutyric acid derivative * * · * · *. , • ·

Three options are shown in the reaction scheme below:

(I) (R = _CH3)

Method Acl, using a mixture of acetone and chloroform, is preferred when R is methyl because good yields are obtained; in one variation thereof, the product of the reaction of acetone with chloroform of the formula can be temporarily isolated

CH ₃ .Cl HO-CC?

CH ₃ XU which is then reacted with the hydroxyacetone of formula VII in an alkaline medium. .

Example

Preparation of 2- [4- (p-chlorobenzoyl) phenoxy] -2-methylpropionic acid

A 20 L flask was charged with 12 L of anhydrous acetone, 1.395 kg of 4'-chloro-4-hydroxybenzophenone, and 1.44 kg (36 moles) of sodium hydroxide. The mixture was heated at reflux for 2 hours to give the phenolate and immediately after removal of the heat source was added a mixture of 2.16 kg (18 mol) of chloroform diluted with 3.5 L of acetone.

This addition is sufficient to maintain a reflux that is maintained for at least 6 hours. Then, while 1/4 of the mixture is still to be added, the reaction mixture will start to heat again due to the diminishing exotherm of the reaction to maintain reflux for 6 to 8 hours after the addition is complete. The reaction mixture is then cooled, the precipitated sodium chloride is filtered off, leaving the sodium salt of the produced acid dissolved in acetone. The acetone is evaporated under reduced pressure and the residue is dissolved in as little lukewarm water as possible at a temperature of about 35 ° C. The aqueous phase is carefully washed three to four times with dichloroethane and then acidified with hydrochloric acid to pH 1 while cooling. The reaction mixture from which the produced acid begins to precipitate is stirred vigorously for 30 minutes, then the acid is suction filtered and washed thoroughly with water. and then dried. Yield 1.61 kg, 85%. The melting point of the acid is 182 ° C.

This acid still contains a small amount (3-4%) of unreacted phenol, all other impurities being removed by the above-mentioned simple treatment, purification of the obtained sodium bicarbonate acid to remove the unreacted phenol is unnecessary, which is industrially very advantageous. For purification, the acid obtained is recrystallized from toluene, thereby raising its melting point to 85 ° C.

? ^H 3

The Ac2 method using Br-C-COY, wherein bromine can be replaced with chlorine i

or iodine, is particularly suitable when R is hydrogen or when one of X '

Xg or Xj of group A is a NOg or CFy residue

This condensation is carried out in ethanol or isobutyl methyl ketone in the presence of potassium carbonate.

Example

Preparation of ethyl 2- [4- (p-chlorobenzoyl) phenoxy] propionate

A 2 L flask was charged with 0.75 mole (175 g) of 4'-chloro-4-hydroxybenzophenone, 1.5 l of methyl isobutyl ketone, 0.975 mole (134 g) of potassium carbonate and 0.8 mole (145 g) of ethyl- 2-bromopropionate. The mixture was heated at reflux for 8 hours with vigorous stirring, then cooled and filtered through a Buchner funnel. Then the solvent was evaporated under reduced pressure and the residue was distilled. The ester produced is collected at a temperature of 98 to 201 ° C at 1 mm Hg. Yield: 190 g (76%).

Regarding the reaction which uses a 2-hydroxyisobutyric (method Ac3) regards dehydration, which may be carried in a medium of dimethylformamide or toluene under acid conditions (H ₂ SO ^, p-toluenesulfonic acid) or under basic conditions, wherein the first embodiment is a preferred variation. This procedure is described in German Patent Publication P 2112 272 5.

A preferred variation using a mixture of acetone and chloroform yields an acid of the formula

which is optionally converted into an amide or ester.

The conversion of acids of formula I into amides and esters is generally described below.

Conversion to amide or ester (case of tertiary alcohol, alkoholamide or 3-pyridylmethanol)

Acid chloride is first prepared from the corresponding acid and phosphorous chloride at low temperature (0 to +5 ° C). This is then reacted with the desired amine or alcohol in the presence of a tertiary amine (triethylamine or pyridine) to neutralize the resulting hydrochloric acid.

Example

Preparation of the amidoester of formula

g (0.1 mol) of 2- [4- (p-chlorobenzoyl) phenoxy] -2-methylpropionic acid is suspended in 250 ml of anhydrous toluene, the resulting suspension is cooled in an ice bath and 20 g of phosphorus pentachloride are added in small portions. The mixture is allowed to stir at this temperature and once all is dissolved, the toluene and the resulting phosphorus oxychloride are evaporated under reduced pressure. The solid residue, m.p. 80 DEG C., which is the acid chloride, is recrystallized from hexane.

After purification, it is dissolved in as little toluene as possible, 8 g (0.1 mol) of pyridine are added and in small portions 13 g (0.1 mol) of 4-hydroxy-N, N-dimethylbutyramide. The reaction is completed by heating in a water bath at 50 ° C for 1 hour, then allowed to cool, pyridine hydrochloride is filtered off, the organic phase is washed with water, dried, decolorized and the solvent is evaporated under reduced pressure. 35 g (22% of theory) of the ester produced, m.p. 92 DEG C., crystallized by evaporation.

Conversion to ester (from secondary or primary alcohol)

It works by direct esterification, which has been thoroughly studied and adapted to the use of secondary alcohol and later also primary alcohol with faster kinetics; this method consists of esterifying a relatively small amount of the selected alcohol: 1 to 1.5 liters of alcohol per kg of acid of formula I and 0.6 kg of sulfuric acid per kg of acid of formula I.

Example

Preparation of isopropyl 2- [4- (p-chlorobenzoyl) phenoxy] -2-methylpropionate kg of the previous acid is suspended in 1.5 L of isopropanol. 600 g of sulfuric acid are slowly added to the suspension and the mixture is refluxed for 12 hours. The reaction mixture was then allowed to cool, whereupon the ester crystallized, which was filtered off with suction, washed with 1 N sodium hydroxide solution with vigorous stirring, filtered again with suction and recrystallized from 1.5 l of isopropanol in the presence of activated carbon. 1.020 kg of recrystallized pure product is obtained having a melting point of 80 ° C. Yield: 85%.

Conversion to ester (using aminoalcohol or alkoholamide)

It is, of course, possible to proceed through the acid chloride, but a preferred method is the transesterification, which is carried out from a simple ester (e.g. methyl ester) and the selected amino alcohol or alkoholamide. The catalyst may be sodium, a metal isopropylate (preferably titanium isopropyl), or p-toluenesulfonic acid.

Example

Preparation of diethylaminoethyl 2- (p-benzoylphenoxy) -2-methylpropionate

CH,

I ³ c-co ₂ -ch ₂ -ch ₂ -n / ^C 2 ^H 5.

CH,

In a 500 ml flask was added 299 g (1 mol) of methyl 2- (p-benzoylphenoxy) -2-methylpropionate, 30 g of titanium (IV) isopropylate and 117 g (1 mol) of diethylaminoethanol. The mixture is heated at 120 ° C (internal temperature) for 45 minutes while distilling off the alcohol formed. The mixture was allowed to cool and poured into 10% hydrochloric acid in the presence of ether. The aqueous phase is basified with methylene chloride. The organic phase is washed extensively with water, dried, decolourised and concentrated under reduced pressure. The oily residue is an ester produced. Yield: 264 g (69%). After conversion to maleate, m.p. 62 ° C.

As for the hydroxyketones of formula

(VII) Common starting materials for all products prepared by the described Ac methods are obtained by one of the following methods:

(a) - Friedel-Crafts method:

This involves using one of the following two methods:

X "

AC-CI + II o ₃

Cl c-Zv- och, ^demeth y y ^ace ,

II = t = / ⁰ 1

OCH, (VII), 2

Such a method for the first stage has already been described in paragraph Aa.

The second step, demethylation, is carried out using 43% hydrobromic acid or aluminum chloride or pyridine hydrochloride.

The following example illustrates the method in more detail, but does not limit it.

Example

Preparation of 4'-chloro-4-hydroxybenzophenone

To a 5 L reaction vessel was added 510 g (3.82 mol) of aluminum chloride, then 3.5 L of anhydrous methylene chloride, and 430 g (4 mol) of anisole was slowly added. The reaction mixture was cooled to maintain the temperature at about 25 ° C, after which 600 g (3.44 mol) of 4-chlorobenzoyl chloride was added dropwise. The mixture was heated at reflux for 6 hours, then allowed to cool to 25 ° C, then the reaction medium was poured onto a mixture of 5 kg of ice and 0.5 L of concentrated hydrochloric acid. The mixture is stirred vigorously during this hydrolysis. The methylene chloride phase is decanted, washed once with water and poured into another 5000 ml reaction vessel. The methylene chloride was distilled off and replaced with 2 L of chlorobenzene. A Dean-Stark well condenser is fitted and the mixture heated to dehydration. Once this step is complete, the mixture is cooled to 50 ° C and 800 g (6 moles) of aluminum chloride is added. The mixture was heated at very gentle reflux for 1.5 hours. Demethylation proceeds rapidly. The mixture was cooled and poured onto a mixture of 6 kg of ice with 0.5 L of concentrated hydrochloric acid. After stirring for 1.5 hours, the precipitate formed is filtered off, washed with water and then with methylene chloride and then dried. Yield: 720 g (90% of theory). Melting point 178 ° C.

(b) - Methods using an organometallic compound

It is the use of the methods described in the preceding paragraph Ab or in the following paragraph Bal (organolithium compounds). Below is a reaction scheme for these methods and an example that illustrates them in more detail without restricting them.

, M _and Br A ^and 'Li

X and ₃

Example

Preparation of 3 ^, -trifluoromethyl-4-hydroxybenzophenone ml (0.15 mol) of n-butyllithium in ether was cooled to -70 ° C and 34 g (0.15 mol) of 3-trifluoromethylbromobenzene was added dropwise. The mixture was stirred at -70 ° C for 5 minutes after the addition was complete, and 23 g (0.15 mol) of sodium 4-methoxyphenylcarboxylate were added at this temperature. The mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. It is then hydrolyzed, extracted with ether and the ether phase is washed with water, dried, decolorized and evaporated. An oil is obtained as a residue which crystallizes in hexane. Yield: 32 g (76%). Melting point 65 ° C.

For demethylaoi, the obtained 32 g of crystalline product was heated with 170 g of pyridine hydrochloride for 30 minutes under reflux. The mixture was allowed to cool, taken up in 10% hydrochloric acid and extracted with ether. The ether phase is then extracted with 2 N sodium hydroxide and acidified. The product melts at 129 ° C. Yield 28 g.

(y) - Method using a bulk derivative

This method can be illustrated by the following reaction scheme:

X ₄

Example

Preparation of 4- (α-thenoyl) phenol

O

In a 250 ml flask, a mixture of 20 g of 4- (α-thenoyl) -bromobenzene, 4 g of anhydrous copper oxide and 10 g of sodium methylate in 130 ml of anhydrous methanol was refluxed for 20 hours. The mixture was filtered the next day and the methanol was evaporated. 15 g (4-n-thenoyl) or sol having a melting point of 73 DEG C. is obtained, which is demethylated with aluminum chloride in chlorobenzene as described above. 13 g (85% of theory) of the phenol produced, m.p.

(δ) - Special case

Preparation of a compound of formula ^X 3 ^X 5 wherein at least two of the substituents are methoxy.

In the first stage, the ether used cannot be methyl ether, so it is prepared by one of the three methods (α, β orγ) tert-butyl ether:

from which, for example, p-toluenesulfonic acid, a hydroxyketone of the formula VII is obtained, in which X1, X8 or X1 is methoxy.

(e) - Methods where no ether is used

The OH group of the compound of formula VII is already present in the starting compound; (or: directly according to the reaction scheme)

This method yields very good yields when A is an alkyl radical.

e ₂ t via a sulfo-containing derivative as an intermediate

C - / K - SO, H A - C - / - OH

taveni

I \ fc /

O Γ via an NOg / + Lno ₂ - ac-AOH group intermediate

J W II W

1 by ^{1 x} 4 * 4

This method is interesting in that it can also obtain the product of formula I with an OH group as a substituent (for example Xj, Xg or Xj of group A). It has been mentioned several times and is exemplified by two examples.

Example

Preparation of 4'-chloro-4-hydroxybenzophenone

A 500 ml flask was charged with 250 ml of dimethylsulfoxide, 4.8 g (0.2 mol) of sodium hydride, then heated at 70 ° C for 1 hour until the solution became clear. Then 24.2 g was added dropwise. (0.2 mol) of benzaldoxime in 100 ml of dimethylsulfoxide. The mixture is kept at 70 ° C for 1 hour and then allowed to cool to 15 ° C. A solution of 26 g (0.1 mol) of 4'-chloro-4-nitrobenzophenone in 150 ml of dimethylsulfoxide is then added. The mixture was stirred at room temperature for 20 hours, poured into acidified water, extracted with ether, and the ether was extracted with 2 N sodium hydroxide. After acidification, 15 g (yield: 65% of theory) of the product with a melting point of 178 DEG C. are precipitated.

Example

Preparation of isopropyl 2- [4- (4-hydroxybenzoyl) -2-phenoxy] -2-methylpropionate

The procedure is the same as above; however, to avoid saponification of the ester group of the starting compound of the formula

this was dissolved in dimethylsulfoxide at +8 ° C and benzaldoxime sodium suspended in dimethylsulfoxide was added in small portions (first stage of preparation). Further processing is the same as in the previous example and the product is obtained in a yield of 76% of theory. Melting point 124 ° C

Table XV below summarizes all the hydroxyketones used, the process for their preparation, and those that are new.

B - Preparation of compounds of formula I via intermediates with a potential carboxyl group

A potential carboxyl group is a group in which a kerboxyl group may be formed. The selected potential carboxyl group is isobutyraldehyde, protected in the form of acetal

CH ₃ 0Y ₃

.... OCC - OY ¹ \ ³ • D LI wherein Y ₃ is alkyl of 1 to 4 carbon atoms, preferably the ethyl radical, in order to use longer mentioned procedures a) and b).

Ba1 - Procedures in which organometallic compounds are used

It utilizes the properties of organometallic compounds which, according to the tonne, when reacted with nitrile, acid chloride or, as a result, the ketones of the formula VIIIa are obtained as intermediates.

CH,

I / ^OY 3 iC-ø Vo — C —OY,

Hydrolysis of the acetal of formula VIII regenerates the aldehyde, which is then subjected to esterification or amidification.

by their nature they provide carboxylic acid salts;

(VIII) is oxidized to an acid,

Bal Method:

Use of organolithium compound

The reaction procedure is shown in the following scheme (wherein Y ₃ is ethyl).

^X CH, 'r.

, Na -CN

CH, oc UI® CH,, / K | ³ 2 ^H 5 butyl- | ³ / ^OC 2 ^H 5 A-CO

Br-f, V-C-C-C — OC, Hc 773 * Li — V y — O — C — C - OC, Hc - ~

Vj-Z I \ h ^{25, thlUm} | ⁵ or A (IX) ^A- c

CH,

AT? θ ^Η 3 ΐ ³ f> -OC-Cl-OC ₂ H _R ACf VOCCH

O R θ

A-C

II o

KMnO.

X _r

R (X)

CH,

IOV ⁿ 3

M = / I

E

C-CO ₂ H

Compound (IX) is charged with lithium with butyllithium in ether at a temperature in the range of -70 to 0 ° C; the product so obtained is reacted with the sodium salt of A-COgH (or the appropriate nitrile) at room temperature. The ketone of formula (X) thus obtained is liberated by acid treatment with ketone aldehyde, which is oxidized with potassium permanganate. The acid obtained is then esterified or amidified as described above.

Compounds of formula (IX) are novel and are generally obtained according to the following reaction scheme:

ch ₃

Br - C - CHO ^ettlyl orthoformiat

R ch ₃ oc ₂ h ₅

Br-C -CH I \

R

OCjHg

Br

OH ”(IX)

-A-oh

As already mentioned výěe (paragraph Ab) can be obtained directly by this method a compound of formula X in which A represents a group of formula ^X 1 wherein X i, X ₂ ⁿ ®Do Xj represents NHG or OH; the latter are obtained from the corresponding nitrated derivative (X ^, Xg or X ^ = NOg).

Ba2 method:

Use of organomagnesium compound

Br AOC-CRF ⁰ ^ ^5, BrMg

CH,

I / OC-CH ₂ h ₅

ACOCI _r

A-CN

The organomagnesium compound can be obtained from the compound of formula IX either directly (Mg in ether or tetrahydrofuran), or by reaction with methylmagnesium iodide. The condensation of this organomagnesium compound with the acid chloride or nitrile is the same as in Ab.

It is understood that compounds of Formula X wherein X _1, Xg and Xj represents OH or NHG, can be prepared only from the corresponding nitro derivative.

Bb - Procedures using hydroxyketone

It is a simple condensation of hydroxyketone with brominated acetal in an alkaline medium according to the reaction scheme

CH, + + - - - - ^OC 2 ^H 5

A-C-Y-OH + Br-C-CH

I \ -l- />

CH, ^X ° ^C 2 ^H 5 CH ₃ followed as described in Ac for the compound of formula Br-C-COX. The thus obtained condensation product of formula X is treated as above to give a compound of formula I.

C - Method to obtain compounds of the formula I in which Xq is -O (CH 2) 2 -O- (1,3-dioxolanyl derivatives)

These compounds are obtained by the action of ethylene glycol in the presence of p-toluenesulfonic acid on compounds of formula I in which Χθ is oxygen and Y is not hydroxyl. Since 1,3-dioxolanyl derivatives are obtained, the corresponding acids (Y = OH) cannot be saponified by, for example, dioxolanyl ester. It is necessary to stop at an alkaline salt (Χθ = -0 (0Η ₂₎ 2θ-, Y = OK, ONa), or by acidification of the salt formed opens before dioxolane ring, thus forming yet acid-ketone.

The process according to the invention for the preparation of the phenoxyalkylcarboxylic acid derivatives of the general formula I is exemplified by the following examples.

Example 1

2- [4 - (“- p-Chlorophenyl -) - α-hydroxyniethyl] phenoxy-2-methylpropionic acid isopropyl ester

CI-ΖΛ

CH (O

OH ČH c-co ₂ -ch .CH,

CH,

350 g of 2- [4- (p-chlorobenzoyl) phenoxy] -2-methylpropionic acid isopropyl ester is dissolved in a Erlenmeyer flask in 4200 ml of methanol. To the resulting solution was added 60 g of potassium borohydride KBH4 and the mixture was stirred at room temperature for 8 hours. The methanol was evaporated and the residue was taken up in water and methylene chloride. The organic phase is washed with water until neutral, then dried and the methylene chloride is evaporated off under reduced pressure.

The very clear oily residue is almost always of high purity and can be used for all purposes as recovered. The yield is quantitative (if a small amount of the starting ketone remains, it can be easily removed by simple treatment with the Girard reagent).

n? ° = 1.5428

Example 2

2- [4- (α-p-chlorophenyl) -α-hydroxymethyl] phenoxy-2-methylpropionic acid

The ester obtained in Example 1 is hydrolyzed with 4 N sodium hydroxide solution for 6 hours at a temperature ranging from 80 to 85 ° C to give the title acid of the above formula, m.p. 132 ° C.

Table I

COY melting point (° C) or continuation of Table I

_fed Product _6No AND ^X 4 ^X 5 R Y at other physical property as stated A-1 88 O H H CHg OH 130 A-2 153 Cl-fy H H CHj OH 185 A-3 162 «-Fy H H ch ₃ och ₃ 89 A-4 163 α-θ- H H ch ₃ oc ₂ h ₅ 79 A-5 170 Cl-ff— H H ch ₃ -Ό 160 A-6 171 ^c, ^ O ' H H ch ₃ -O 148 A-7 178 "O- H H ch ₃ ^CH 3 OCH ^x CH ₃ 80 A-8 180 O H H ch ₃ och ₃ 58 A-9 186 O-' H H ch ₃ OC ^ 87 A-10 190 and H H ch ₃ / ^GH 3 -O-CH ^x CH ₃ 84 A-11 208 H H ch ₃ -O (CH ₂ ) ₂ -NH 2. fumarate 100 ALIGN! A-12 209 and H H ch ₃ -O (CH ₂ ) ₂ -No fumarate 118 A-13 211 and H II ch ₃ -q (CH ₂ ) ₂ -N ₍ fumarate 115 A-14 212 and H H ch ₃ / ^C 2 «5 -O (CH _{2) 2} -N-maleate 62 ^G 2 ^H 5 A-15 217 ^c, -O H H ch ₃ -? -? -? , 35 A-16 229 a ^ Q- H TO ch ₃ -O (CH ₂ ) ₂ -N ^ ₂ fumarate 122

2.2252 continued Table I melting point (° C) or other physical property as indicated

Product code number

A-17

A-18

A-19

A-20

A-21

A-22

230

231

238

239

253

259

H

H

H

H

H

H

C, H _K / 25

CH 2 -O (CH 2) - N, HCl

2 d \ ¹ ^ 5

O

CH ₂ -O (CH ₂ > ₂ N, fumarate

-O — CH,

104

116

CH,

144

_CH3 -OlCH _{2) 2} -N ^ J> _T HC1

145

CH,

CH, .CH,

-O-CH'CH, boiling point:

220 ° C / 0.1 tor

CH, oil - o (ch ₂ ) _{3 -} o ₂ c - c - o

CH,

A-23

A-24

Δ-25

A-26

A-27

A-28

A-29

A-30

A-31

328

340

384

385

386

387

388

401

402

About ^-

Cl

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

FROM ^C 2 ^H 5

CH, -NH- (CH3), N, fumarate c ₂ h ₅

CH ₃ -o - (- CH ₂ ) ₂ -NJ oxalate

CH ₃ -o-ch c ₇ h ₁₄

CH ₃ - ° - ^C 12 ^H 25

CH,

CH,

CH,

CH,

CH,

176

125

-sc ₂ h ₅

-N / ^C 2 ^H 5 c ₂ h ₅

-00 ₈ Η ₁₇

OH / CH ₃ -O-CH

117 n ₂₀ = 1.535

196, 15 continued Table I

NET * * * 4 ^x 5

Cl

A-32,403

A-33, 404

A-34405

Η H CH,

Η H CH,

Η H CH,

-O-CH-CH, ^X _CH3

OH

-OH,

-O-CH-OH,

A-35,406

A-36 507 '

1-37 512

Cl

Cl

3-CH ₃ 5-CH ₃

3-CH ₃ 5-CH ₃ CH ₃

Η H CH,

Η H CH,

CH,

OH

OH • CH,

-O-CH'CH,

OH

A-39 518

A-40 573

A-41 573

A-42 575

A-43,590

A-44560

A-45606

A-46606A

A-47,607

Η H CH,

Η H CH,

Η H CH,

Η H CH,

Η H CH,

Η H CH,

Η H CH,

Η H CH,

Η H CH,

-O-CH '

OH

-CH, CH,

OH

OH

- CH,

-O-CH '• CH,

OH melting point (° C) or other physical property as indicated

155

121

182

144

130

114

129

182

120

126 Continuation of Table I Melting point (° C) or other physical property as specified

Product code number

X ₄ x ₅ R

A-48

A-49

A-50

A-51

A-52

A-53

A-54

A-55

A-55bis

A-56

A-57

A-58

Λ-59

A-60

A-61

A-62

611

618

619

627

634

398

399

624

CH,

CH,

CH,

CH,

CH,

CH,

CH,

ci / A

CH,

CH,

CH,

CH,

CH,

120

158

OH

oc (ch ₃ ) ₃ OCH ₃ [| ° x ° h ₃ c ch ₃

OH

OCHgCHCHgOH

160

124

192

146

120

176 n _D = 1.5535 o (ch ₂ ) ₂ con (ch ₃ ) ₂ 90

OH

108 och (ch ₃ ) ₂ "20, 516 melting point (° C) or other physical property as specified

Product ^AX 4 ^X 5 ^R continued Table I

A-63

A-64

A-65

H ₃ CO

129

OCH _{(CH3) 2} OCH _{(CH3) 2}

A-68 559 (CH ₃ ) ₂ -CH- H H ch ₃ A-69 538 (CH ₃ ) ₂ -CH- H H ch ₃ A-70 637 "O H H CH ₃ A-71 639 ^or O H H ch ₃ A-72 - d ^ y H H CH ₃ A-73 - ^ci -cy H H ch ₃ A-74 - H H ch ₃ A-75 - H H ch ₃ A-76 - H H ch ₃ A-77 - O H H ch ₃ A-78 -O H H ch ₃

OH - OCH _{(CH3) 2} - / ^C 2 ^H 5 -NH (CH 2) _O -N ^ 64 2 2 ^C ^ 5 ch ₃ -0- (CH _a), - C0N 2 3 \ ₃ ^x CH 92 -0-CH _(CH3) C ^ CJ = CH₃ 55 -o-ch (c ₂ h ₅ ) ₂ 67 -O-CH (CH ₃ ) CH ₂ CH ₃ 82 ° ^C 8 ^H 17 38 . "= I 114 O- (CH ₂ ) ₂ -, Y, HCl 138 / - \ —N 0 160

continuation of Table

Product code Number ^é A ^X 4 ^X 5 R Y melting point <° C) or other physical property, as stated A-79 - H H ch ₃ -0-0) 2¼ 37 A-80 - ^{, r} O H H ch ₃ -O- (GH ₂ ) ₂ -N, HCl hygroscopic A-81 - H H ch ₃ -O- (CH ₂ ) ₂ -. HCl 125 A-82 272 and H H H -O-tc-Ig-O-fumerate 110 A-83 391 cyclohexyl H H ch ₃ OH 148 A-84 390 cyclohexyl H H ch ₃ O-CH _{(CH3) 2} 67 A-85 - 4-CH 0C ₆ H ₄ H H ch ₃ O-C18 38 A-86 - 4-CH ₃ OC ₆ H ₄ H H ch ₃ O-CH (CH ₃₎ C ₂ H ₅ 74 A-87 - 4-ClC ₆ H ₄ 2 ICH-j 6ÁCH ₃ ch ₃ 0-CH _{(CH3) 2} 70

Table 11

CH,

AND

O-CH-CO-Y

AND

R

Product ^X 1 ^X 2 ^X 3 ^X 4 ^X 5 R R ' Y B-1 (a) 4-C1 H H H H ch ₃ H OCH _{(CH3) 2} B-2 4-C1 H H H H CH, H OH B-3 (o) 4-C1 H H H H ch ₃ CH, OH B-4 4-C1 H H H. H ch ₃ ch ₃ OCH _{(CH3) 2} B-5 4-C1 H H H H ch ₃ coch ₃ OCH _{(CH3) 2} B-6 4-C1 H H H H ch ₃ H och ₃ B-7 4-C1 H H H H CHj H OC ₂ Hg B-8 4-C1 H H H H ch ₃ H -O B-9 4-C1 H H H H CHj H —TS 'p B-10 H H H H H ch ₃ H OH B-11 H H H Η H CH ₃ H och ₃ B-12 H H H H H CH ₃ H OCjjHg B-13 H H H H H ch ₃ H OCH _{(CH3) 2}

continuation of Table II

Product ^X 1 ^X 2 ^X 3 ^X 4 ^X 5 R R ' Σ B-14 H H H H H ch ₃ H Ο (CH ₂ ) ₂ - ·θ · fumarate B-15 H H H H H ch ₃ H O (CH ₂ ) ₂ -N ^/ O fumaret B-16 H H H H H ch ₃ H q (CH ₂ ) ₂ -IV, fumaret B-17 H H H H H ch ₃ H O (Cl 2) ₂ --NC ₂ B 1 - _2r malate B-18 4-C1 H H H H CH, H O-AA-CI \ = / 0 (ch ₂ ) ₂ -n J B-19 4-C1 H H H H CH ₃ H 7 /, fumaret B-20 4-C1 H H H H CH ₃ H 0 _(ΟΗ?) Η _{3 (0? 5 Η)?} , HCl B-21 4-C1 H H 3-CH ₃ H CH ₃ H OCH _{(CH3) 2} B-22 4-C1 H H H H CH ₃ H oyklooktyloxyl B-23 4-C1 H H H H CH ₃ H B-24 4-C1 H H H H CH ₃ H OCCH2CH3 B-25 2-C1 6-C1 H H H CH ₃ H OH B-26 2-C1 6-C1 H H H CH ₃ ch ₃ OH B-27 2-C1 6-C1 H H H CH ₃ Η OCH _{(CH3) 2} B-28 2-C1 6-C1 H H H CH ₃ ch ₃ OCH _{(CH3) 2} B-29 3-C1 H H H H CH ₃ Η OH B-30 3-C1 H H H H CH ₃ ch ₃ OH B-31 3-C1 H H H H CH ₃ Η OCH _{(CH3) 2} B-32 3-C1 4-C1 H H H ch ₃ Η OH B-33 3-C1 4-C1 H H H ch ₃ Η OCH _{(CH3) 2} B-34 4-Br H H H H ch ₃ Η Okay B-35 4-Br H H H H CH, ch ₃ OH B-36 4-Br H H H H CH ₃ Η OCH _{(CH3) 2} B-37 4-C1 H H 3-CH _{3 5-CH3} CH ₃ Η OH B-38 4-C1 H H 3-CH _{3 5-CH3} CH ₃ Η OCH _{(CH3) 2} B-39 4-OCHj H H H H ch ₃ Η 0Η B-40 (h) 4-OCH ₃ H H H H ch ₃ Η OCH _{(CH3) 2} B-41 2-C1 H H H H ch ₃ Η OH 8-42 2-C1 H H H H ch ₃ Η OCH _{(CH3) 2} B-43 _2-CH3 H H H H CH ₃ Η OH B-44 _2-CH3 H H H H οη _ί Η OCH _{(CH3) 2} B-45 4-NO ₂ H H H H CH ₃ Η OH B-46 4-NO ₂ H H H H CH ₃ Η OCH _{(CH3) 2} B-47 _{2-CH3 6-CH3} H H H CH ₃ Η OH B-48 4-NH2 H H H H ch ₃ Η OH B-49 4-NH, H H H H CH ₃ Η OCH _{(CH3) 2} B-50 4-F H H H H CH ₃ Η OH B-51 4-F H H H H ch ₃ Η OCH _{(CH3) 2} B-52 4-OH H H H H ch ₃ Η OH B-53 4-OH H H H H ch ₃ Η OCH _{(CH3) 2} B-54 4-C1 H H H H H Η OH B-55 4-C1 H H H H H Η och (ch ₃ > ₂

21Ž252 continued Table II

Product X, x ₂ ^x 3 ^X 4 ^X 5 R R ' Y CH, / 3 B-56 4-CI H H H H CH, H OCH ^ 2 * 5 X ^Cíi 3 B-57 4-CI H H H H CH ₃ CH ₃ OCH ^ 2 * 5 B-58 4-C1 H H H H CH ₃ H oc (ch ₃ ) ₃ B-59 4-CI H H H H CH ₃ H OCHgCHOHCHgOH B-60 4-CI H H H H ch ₃ H O (CH 2) ₂ CON (CH ₃ ) ₂ B-61 3-CF ₃ H H H H CH ₃ H OH B-62 3-CF ₃ H H H H CH ₃ H OCH _{(CH3) 2} B-63 3-OCH ₃ 4-OCH ₃ 5-008 ^ H H CH ₃ H OH B-64 3-OCH ₃ 4-OCH, 5-OCH ₃ H H CH ₃ H OCH _{(CH3) 2} B-65 3-OCH ₃ 4-CI H H H ch ₃ H OH B-66 3-OCH ₃ 4-CI H H H CH ₃ H OCH _{(CH3) 2} Note: (a): n = 0 = 1.5428; (b): t - t - 132 [deg.] C .; | (o): m.p. . = 99 ° C; (d): «20 D = 1.5532; (e): mp = 122 ° C; (F) “20 • ⁿ D” 1,550; (g): m.p. = 120 ° C; Ch): « ^{2θ n} D = 1.543. Table III

C ^h 3 -O-C-COY ^X 4 1 R OF ^X 4 X ₅ R Y melting point (° C)

NO. 1

C-2

ΗH CH3 OH

Η H CH ₃ OCH (CH ₃ ) ₂

C-3

574

Cl C H H CH ₃

OH

162

C-4

HH _CH3

OCH (CH ₃ ) ₂ continuation of Table III

Product code number OF ^X 4 C-5 - Br-IjLcO- H C-6 - Br-ith ^ jLcO- H C-16 640 H ch ₃ . / ^CH 'ch ₃ / CH, ¹ ΖΛ -o, c — c — o— <! τ- Ι CHj -C II O C-7 491 QLco- H C-8 493 H C-9 515 H C-IO - jLco- H C-11 - ^Br -k, _on Jl. ^c ° - H C-12 541 BrJjLcO- H C-13 612 _n —r ^co H C-14 WHAT l 1 A H C-15 HO ₂ C ⁰ c ₂ h ₅ CH ₃ —c -oY> c- H CHj 0

H

H

H

H

H

H

H

H

H

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

Y melting point (° C)

OH

OCH _{(CH3) 2}

OCH _{(CH3) 2} 72

OH 156

OCH (CH ₃ ) ₂ 63

OH 131 and (ch ₃ ) ₂

OH

OCH _{(CH3) 2} 72

OH 132

OCH (CH ₃ ) ₂ n = ⁰ = 1.5455

OH 185

Table IV

continuation of Table IV

AND ^X 4 ^x 5 melting point (° C> spdsob preparation ⁺ ^ - < ^CH 3 CH ₃ H H 155 and ° 2 ^N - ^ 2y ~ H H 190 and H H 139 P ^CF 3 Q H H 98 P OHC H H 164 'P H H 190 P H H 139 a, γ ÍM ,, H H 124 and at H H 88 a, Y 4-chlorophenyl 3-CH _{3 5-CH3} 98 and

Note: + new compounds

Claims (1)

A process for the preparation of novel phenoxyalkylcarboxylic acid derivatives of the general formula II, CH, i O-C-CO-Y AND R (II) where * A represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or cyclohexyl, or one of the groups of the formulas wherein each of X? Z ₂ and Xj are the same or different, is hydrogen, chlorine, bromine, fluorine, , trifluoromethyl, amino, hydroxyl, C1-C4alkyl, C1-C4alkoxy, benzyloxy, acetylamino, acetoxy, CHO, COOH, -OCCCH3Jg-COM, where M is hydroxyl or (C1-C4) alkoxy, Xg is oxygen or sulfur and γ is hydrogen, chlorine or bromine, each of R, X4 and X4, which are sodium or different, is hydrogen or C1-C4alkyl; carbon atoms, Y is hydrogen, hydroxyl, straight chained or branched chain alkoxy of 1 to 12 carbon atoms, cycloalkyloxy of 3 to 8 carbon atoms, alkylthio of 1 to 4 carbon atoms, 2,3-dihydroxypropyloxy, 4- (2,2-dimethyl) -1,3-dioxolenyl) methyleneoxy of formula -O-CH ₂ ° x ° C H ₃ CH _3, phenoxy, optionally substituted by chlorine in position 4, then 3-pyridylmethylenoxyskupinu, 5- (2-methyl-3-hydroxy-4-hydroxymethylpyridyl) methylenedioxy group of the formula ΝΖ, Ζ ^ NHCHgCHgNZjZg , OCl ^ CI ^ NZ ^, OCCH ^ CONZ ^ g, wherein a is 1 to 4 and each of Z, and Zg is either C 1 -C 4 alkyl, or Z, and Zg together with the nitrogen atom form to which they are bound, an N-heterocyclic group of 5 to 7 members which optionally contains oxygen, nitrogen or sulfur as an additional heteroatom and which is optionally substituted by a C1-C4 alkyl radical or a phenyl radical optionally substituted by halogen, or a group of formula ch ₃ Cl - o - (ch ₂ ) _{3 -} o ₂ c - co C ₃ and R "represent a hydrogen atom, a C 1 -C 4 alkyl group or an acetyl group as well as their editorial salts, characterized in that a compound of the formula I is reduced by the action of a reducing agent, CH ₃ A-C O-C-CO-Y X 212252 kde A, X ^, X ^, R a and Y are as defined above, and the resulting product of formula (II) wherein R 'is hydrogen and A, X ^, X ^ and X are as previously defined are optionally etherified or acetylated reaction, whereby the product obtained is optionally converted into an addition salt